CN110087698B

CN110087698B - Medical honeycomb structure

Info

Publication number: CN110087698B
Application number: CN201780077827.4A
Authority: CN
Inventors: 石川邦夫; 都留宽治; 土谷享; 杉浦悠纪; 中岛康晴
Original assignee: Kyushu University NUC
Current assignee: Kyushu University NUC
Priority date: 2016-10-17
Filing date: 2017-10-16
Publication date: 2022-06-24
Anticipated expiration: 2037-10-16
Also published as: US11246708B2; EP3527233A4; CN110087698A; WO2018074429A1; EP3527233A1; JP2022050587A; US20220117741A1; JP7089284B2; EP3527233B1; JPWO2018074429A1; EP3527233C0; US20200046503A1

Abstract

The present invention addresses the problem of providing a medical honeycomb structure that satisfies the following requirements expected for medical materials: (1) excellent adhesion or bondability of cells or tissues to the surface of a material; (2) tissue capable of regenerating and reconstructing orientation; (3) the mechanical strength is excellent; (4) in the case of use as a tissue substitute material, is promptly replaced with a desired tissue; (5) can be produced at low cost. The solution of the present invention is a medical honeycomb structure including a plurality of through holes extending in one direction, the medical honeycomb structure including, on an outer peripheral side portion thereof: a through hole groove formed by the side wall of the through hole being damaged; and a through-hole entrance adjacent to the through-hole groove.

Description

Medical honeycomb structure

Technical Field

The present invention relates to a medical material and a method for producing the same. More specifically, the present invention relates to a medical material having a honeycomb structure used in the medical field or the medical-related field, for example, in tissue regeneration/reconstruction techniques for bones and teeth, or in scaffolds for regenerative medicine, and a method for producing the same.

Background

In medical and dental clinics, a defective tissue may be regenerated and reconstructed using a medical material. In this case, the medical material may be expected to bond to the surrounding tissue. Important initial steps in the binding of medical materials to surrounding tissue, etc., are the adhesion of cells to the surface of the material, the binding of tissue to the surface of the material. If the medical material is not fixed to the surrounding tissue, it is difficult to cause tissue conduction and cell migration.

Among medical materials, porous materials often exhibit excellent functions because cells and tissues are likely to penetrate into the interior of the porous materials. The porous material can be classified into an independent porous body and a interconnected porous body, and the interconnected porous body, in which cells can invade the inside of the material, is highly useful when substitution of a medical material for a tissue is expected. For this reason, methods for producing a connected porous body by introducing a pore-forming material and burning the material as disclosed in patent documents 1 and 2 have been proposed.

On the other hand, as reported in non-patent document 1, it is known that a tissue such as a bone is variously oriented depending on a site, and a function is improved by the tissue orientation. However, as disclosed in non-patent documents 2 and 3, etc., the regenerated bone lacks in orientation and functionality, and therefore, it is necessary to induce orientation.

As for the orientation-based interconnected porous bodies, methods of manufacturing by applying the principle of frost are proposed as disclosed in patent documents 3 to 7. However, the interconnected orientation porous bodies produced by applying the frost column principle do not necessarily have sufficient orientation. In addition, strict temperature control is required to grow the frost column, and the productivity is insufficient and the manufacturing cost is high. In addition, there are the following serious problems: it is impossible to produce a interconnected oriented porous body having the same morphology.

On the other hand, the honeycomb structures produced by extrusion molding or the like reported in patent documents 8, 9 and the like exhibit ideal orientation-based interconnected porous bodies. However, the honeycomb structure manufactured at present does not necessarily exhibit sufficient tissue-binding ability and cell-adhering ability, and is not a medical material that can satisfy tissue regeneration and reconstruction.

For this purpose, patent document 10 discloses the following technique: the honeycomb structure is cut along a plane parallel to the direction of the through-holes, and a plurality of grooves are formed on the surface of a plate-shaped substrate. The technique disclosed in patent document 10 is superior in adhesion and bondability of cells or tissues to the material surface as compared with a honeycomb structure having peripheral side walls, but since cells or tissues cannot penetrate into the honeycomb structure from the peripheral side walls, functions such as bonding to surrounding tissues cannot be said to be sufficient.

Patent document 11 discloses a technique of forming holes penetrating through an outer peripheral side wall of a honeycomb structure. In this manner, cells and tissues can enter the honeycomb structure from the outer peripheral side wall. Therefore, the technique disclosed in patent document 11 is superior in adhesion and adhesion of cells or tissues to the material surface as compared with a honeycomb structure having no holes in the outer peripheral side wall, but the production cost is extremely high. In addition, the ability of the surrounding tissue to bond to the outer peripheral surface is not sufficient. In addition, the orientation of the surrounding structure at the peripheral sidewall cannot be controlled at all.

Documents of the prior art

Patent literature

Patent document 1: japanese patent No. 3470759

Patent document 2: japanese patent No. 4802317

Patent document 3: japanese patent No. 3858069

Patent document 4: japanese patent No. 3940770

Patent document 5: japanese patent laid-open No. 2008-230910

Patent document 6: japanese laid-open patent publication No. 2010-18459

Patent document 7: japanese patent laid-open No. 2012-148929

Patent document 8: japanese laid-open patent publication No. 2004-298407

Patent document 9: japanese patent laid-open publication No. 2005-152006

Patent document 10: japanese laid-open patent publication No. 2004-298545

Patent document 11: japanese laid-open patent publication No. 2005-110709

Non-patent literature

Non-patent document 1: nakano T, et al, "Unique alignment and texture of biological application crystals in biological analyzed by micro-beam X-ray differential meter system" Bone,31[4] (2002) 479-.

Non-patent document 2: nakano T, et al, "Biological alignment (BAp) crystalline orientation and texture as a new index for assessing the microstructure and function of Bone regenerated by tissue engineering" Bone 51(2012)741-747.

Non-patent document 3: ishimoto T. et al, "gather of biological application c-axis orientation of a vertical Bone minor mechanical function in Bone regenerated used rBMP-2" Journal of Bone and Mineral Research 28(2013)1170-1179.

Disclosure of Invention

Problems to be solved by the invention

In the method for producing the interconnected porous bodies by introducing the pore-forming material and incinerating the introduced material, the non-oriented porous bodies, the porous bodies having insufficient orientation, and the porous bodies having pores without connectivity are produced.

Further, the orientation of the oriented interconnected porous body produced by applying the frost column principle is insufficient. Further, in order to grow the frost column, strict temperature control is required, productivity is insufficient, production cost is high, and there is a problem that it is not possible to produce the interconnected porous bodies having the same uniaxial orientation as the form.

Further, a honeycomb structure produced by extrusion molding or the like is an ideal orientation interconnected porous body, and therefore it is expected to provide a medical material having excellent orientation, but the honeycomb structure provided so far does not necessarily exhibit sufficient cell adhesion ability, tissue bonding ability, and oriented tissue formation ability, and is not a structure that can be produced at a practical production cost.

The present invention has been made in view of the above-described problems, and an object of the present invention is to provide a medical honeycomb structure and a method for manufacturing the same, which satisfy the following requirements desired for medical materials: (1) excellent adhesion or bondability of cells or tissues to the surface of a material; (2) the tissue with orientation can be regenerated and reconstructed; (3) the mechanical strength is excellent; (4) in the case of use as a tissue substitute material, is quickly substituted for a desired tissue; (5) can be produced at low cost.

Means for solving the problems

As a result of intensive studies, the inventors of the present application have found that, by forming: the present inventors have completed the present invention by obtaining a medical material that satisfies the requirements (1) to (5) by forming through-hole grooves, which are formed by breaking the side walls of through-holes constituting a honeycomb structure, and through-hole inlets adjacent to the through-hole grooves.

Namely, the present invention is as follows.

[1] A medical honeycomb structure comprising a plurality of through holes extending in one direction,

the outer peripheral side part of the utility model is provided with: a through hole groove formed by the side wall of the through hole being damaged; and a through-hole inlet adjacent to the through-hole groove.

[2] The medical honeycomb structure according to [1], characterized in that an inclined surface inclined with respect to a penetrating direction of the through-hole is formed at an outer peripheral portion.

[3] The medical honeycomb structure according to any one of [1] and [2], wherein a ratio of a length of the through-hole groove in a longitudinal direction to a length of the through-hole groove in a width direction is 1.5 or more.

[4] The medical honeycomb structure according to any one of [1] to [3], wherein a ratio of the number of through-hole entrances in the outermost layer to the number of through-holes is 0.05 or more.

[5] The medical honeycomb structure according to any one of [1] to [4], wherein the through-hole grooves and the through-hole inlets are provided in at least the outermost layer and the 2 nd outer layer inside the outermost layer.

[6] The medical honeycomb structure according to any one of [1] to [5], wherein a ratio of the uneven surface on the outer peripheral side surface on which the through-hole grooves and the through-hole inlets are formed is 10% or more.

[7] The medical honeycomb structure according to any one of [1] to [6], characterized in that a through-hole penetrating through a side wall of the through-hole is provided.

[8] The medical honeycomb structure according to any one of [1] to [7], characterized in that the diameter of the through-hole is 5 μm or more and 400 μm or less.

[9] The medical honeycomb structure according to any one of [1] to [8], wherein the thickness of the partition walls of the through-holes is 10 μm or more and 300 μm or less.

[10] The medical honeycomb structure according to any one of [1] to [9], characterized in that a ratio of a diameter of the through-hole to a thickness of the partition wall of the through-hole is 0.2 or more and 20 or less.

[11] The medical honeycomb structure according to any one of [1] to [10], wherein a thickness of an outer peripheral side wall of the outer peripheral side portion is 300 μm or less.

[12] The medical honeycomb structure according to any one of [1] to [11], wherein a ratio of a length of the through-holes in a longitudinal direction to a diameter is 3 or more.

[13]Such as [1]]～[12]The medical honeycomb structure according to any one of the above aspects, which is 10^-8m³Above and 10^-3m³The following blocks.

[14] The medical honeycomb structure according to any one of [1] to [13], characterized by being formed of a composition containing at least a calcium compound.

[15] The medical honeycomb structure according to [14], wherein the calcium compound is at least one selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate and calcium-containing glass.

[16] The medical honeycomb structure according to any one of [1] to [15], which is formed of a composition containing at least one selected from the group consisting of apatite, β -tricalcium phosphate, α -tricalcium phosphate, and octacalcium phosphate.

[17] The medical honeycomb structure according to any one of [1] to [16], characterized by being formed of a composition containing carbonic apatite.

[18] The medical honeycomb structure according to any one of [1] to [17], characterized by being formed of a composition containing a polymer material.

[19] [1] A crushed product of the medical honeycomb structure according to any one of [1] to [18 ].

[20]Such as [19]]The crushed material is 10^-12m³Above and less than 10^-8m³The size of (2).

[21] A medical honeycomb structure comprising a plurality of through holes extending in one direction,

the medical honeycomb structure is formed from a composition containing a carbonic apatite.

[22] [21] A crushed product of the medical honeycomb structure.

[23] The method for manufacturing a medical honeycomb structure according to any one of [1] to [18], comprising the steps of:

a structure body manufacturing step of manufacturing a honeycomb structure body having an outer peripheral side wall by extruding a material through a honeycomb structure forming die; and

and an outer peripheral side portion processing step of removing at least a part of the outer peripheral side wall of the honeycomb structure having the outer peripheral side wall and forming a through-hole groove and a through-hole inlet in the outer peripheral side portion.

[24] [19] the method for producing a crushed product of a medical honeycomb structure according to any one of [20], comprising the steps of:

a structure body manufacturing step of manufacturing a honeycomb structure body having an outer peripheral side wall by extruding a material through a honeycomb structure forming die;

an outer peripheral side portion processing step of removing at least a part of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall and forming a through-hole groove and a through-hole inlet in the outer peripheral side portion; and

a crushing step of crushing the honeycomb structure having the through-hole grooves and the through-hole inlets into 10 pieces^-12m³Above and less than 10^-8m³The size of (2).

[25] A method for producing a medical honeycomb structure according to any one of [1] to [17] having a composition containing apatite carbonate, the method comprising:

a structure-with-outer-wall manufacturing step of extruding a mixture in which calcium hydroxide and an organic binder are mixed through a honeycomb structure-forming die to manufacture a honeycomb structure having an outer peripheral side wall;

a degreasing step of degreasing the honeycomb structure;

a carbonation step of carbonating the honeycomb structure simultaneously with or after the degreasing step; and

a phosphorization step of applying a phosphate aqueous solution to the honeycomb structure subjected to the carbonation step,

in any stage after the outer wall-equipped structure manufacturing step, an outer peripheral side portion processing step is provided in which at least a part of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall is removed, and a through-hole groove and a through-hole inlet are formed in the outer peripheral side portion.

[26] A method for producing a medical honeycomb structure according to any one of [1] to [17] having a composition containing apatite carbonate, the method comprising:

a structure body manufacturing step of manufacturing a honeycomb structure body having an outer peripheral side wall by extruding a mixture in which calcium sulfate and an organic binder are mixed through a honeycomb structure forming die;

a degreasing step of degreasing the honeycomb structure; and

a phosphorization step of applying an aqueous solution containing carbonate and phosphate or sequentially applying an aqueous solution containing carbonate and an aqueous solution containing phosphate to the honeycomb structure subjected to the degreasing step,

[27] The method for producing a medical honeycomb structure according to [21], which is characterized by comprising:

a degreasing step of degreasing the honeycomb structure;

and a phosphorization step of applying a phosphate aqueous solution to the honeycomb structure subjected to the carbonation step.

[28] The method for producing a medical honeycomb structure according to [21], which is characterized by comprising:

a degreasing step of degreasing the honeycomb structure; and

and a phosphorization step of applying an aqueous solution containing carbonate and phosphate or sequentially applying an aqueous solution containing carbonate and an aqueous solution containing phosphate to the honeycomb structure subjected to the degreasing step.

ADVANTAGEOUS EFFECTS OF INVENTION

The medical honeycomb structure of the present invention is a structure satisfying the requirements that are desired for medical materials, that is, (1) excellent adhesion or bondability of cells or tissues to the surface of a material, (2) tissue that can be regenerated and reoriented, (3) excellent mechanical strength, (4) being quickly replaced with a desired tissue when used as a tissue substitute material, (5) being able to be produced at low cost; can be widely used in the medical field or the medical-related field.

Drawings

Fig. 1 is a schematic view of a honeycomb structure having an outer peripheral side wall.

FIG. 2 is a schematic view (an example) of a medical honeycomb structure according to the present invention.

Fig. 3 is a schematic view (an example) showing a state where a part of an outer peripheral side wall of a medical honeycomb structure of the present invention is removed.

Fig. 4 is a schematic view (an example) showing a state where a plurality of layers of the outer peripheral side wall of the medical honeycomb structure of the present invention are removed.

Fig. 5 is an explanatory view of through-hole grooves and through-hole inlets in the medical honeycomb structure of the present invention.

FIG. 6 is a photograph of a cylindrical binder-containing calcium hydroxide honeycomb structure having an outer peripheral side wall produced as an intermediate according to example 1 a.

Fig. 7 is a photograph of the honeycomb structure before the degreasing step in example 1 a.

Fig. 8 is an electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step according to example 1 a.

Fig. 9 is a weakly enlarged image of a pathological tissue in a histopathological examination using the honeycomb structure according to example 1b, where (a) is an image obtained by cutting in a direction perpendicular to through holes (cells), and (b) is an image obtained by cutting in parallel with the through holes (cells).

Fig. 10 is an electron micrograph (SEM photograph) of the honeycomb structure particles of example 2.

Fig. 11 is an electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step according to example 3.

Fig. 12 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 4.

Fig. 13 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 6.

Fig. 14 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 7.

Fig. 15 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 9.

Fig. 16 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 10.

Fig. 17 is an electron micrograph (SEM photograph) of the honeycomb structure according to example 11 a.

Fig. 18 is a weakly enlarged image of a pathological tissue in a histopathological examination using the honeycomb structure according to example 11 b.

Fig. 19 is a strongly enlarged image of a pathological tissue of a tissue entering a cell located in a proximal portion of a honeycomb structure from a through-hole entrance in an outer peripheral side portion in a histopathological examination using the honeycomb structure according to example 11 b.

Fig. 20 is an electron micrograph (SEM photograph) of the honeycomb structure particles according to example 12.

Fig. 21 is a weakly enlarged image of a pathological tissue in a histopathological examination using the honeycomb structure according to example 12.

Fig. 22 is a strongly enlarged image of a pathological tissue of a tissue that enters a cell located in a near-center portion of a honeycomb structure from a through-hole entrance that is open in a through-hole direction at an outer peripheral side portion of the honeycomb structure according to example 12.

Detailed Description

[ medical Honeycomb Structure of the present invention ]

A medical honeycomb structure according to the present invention is a medical honeycomb structure including a plurality of through holes (hollow bodies) extending in one direction, the medical honeycomb structure including, on the outer periphery side thereof: a through hole groove formed by the side wall of the through hole being damaged; and a through-hole inlet adjacent to the through-hole groove.

Hereinafter, each configuration will be described.

Honeycomb structure of medical honeycomb structure of the present invention

The honeycomb structure for medical use of the present invention has a honeycomb structure, and the honeycomb structure in the present invention is a structure in which through polygonal hollow pillars or through circular hollow pillars (through holes) penetrating in the major axis direction are arranged without a gap. The through hole and the space formed by both ends of the through hole are referred to as a cell (cell).

In the orientation-based interconnected porous bodies produced by applying the principle of frost as disclosed in patent documents 3 to 7, the frost forming the pores is connected during the formation process or growth of other frost is inhibited, and therefore the honeycomb structure of the present invention cannot be formed. Therefore, the orientation interconnected porous bodies manufactured by applying the frost column principle as disclosed in patent documents 3 to 7 are not included in the medical honeycomb structure of the present invention.

The honeycomb structure of the present invention can be generally formed by extrusion molding or the like. Specifically, for example, a honeycomb structure having an outer peripheral side wall composed of hydroxyapatite and an organic binder (a precursor of the honeycomb structure of the present invention) can be produced by mixing hydroxyapatite powder with an organic binder and performing extrusion molding by a method disclosed in japanese patent No. 3405536 and japanese patent application laid-open No. 10-59784. Further, the honeycomb structure having an outer peripheral side wall composed of the carbonate apatite and the collagen (the precursor of the honeycomb structure of the present invention) can be produced by extrusion-molding the carbonate apatite powder using the collagen as a binder and drying the molded product. The medical honeycomb structure of the present invention can be obtained by removing the outer peripheral side wall of the honeycomb structure having the outer peripheral side wall and forming the through-hole grooves and the through-hole inlets on the outer peripheral side thereof.

Here, an example of a honeycomb structure having an outer peripheral side wall, which is a precursor of the honeycomb structure of the present invention, will be described with reference to fig. 1. As shown in fig. 1, the honeycomb structure 14 having an outer peripheral side wall is a cylindrical body having the following configuration: a plurality of through holes 11 extending in one direction, partition walls 12 dividing the through holes, and an outer peripheral side wall 13 surrounding a honeycomb structure portion formed by the through holes. Hereinafter, if necessary, a direction perpendicular to a penetrating direction of the through hole is referred to as an "a" direction, a surface of the outer peripheral sidewall is referred to as an "a" plane, a penetrating direction of the through hole is referred to as a "C" direction, and a plane formed by an end of the through hole is referred to as a "C" plane. For example, as shown in fig. 1, when the honeycomb structure has a cylindrical shape, the a-plane is a cylindrical side surface and the C-plane is a circle.

< peripheral side wall of honeycomb structure >

Fig. 2 shows a schematic view (an example) of the medical honeycomb structure of the present invention. The outer peripheral side wall of the honeycomb structure 14 shown in fig. 1 is removed. The medical honeycomb structure 10 is obtained by removing the outer peripheral side wall (outer peripheral side portion) of the honeycomb structure having the outer peripheral side wall 13 by grinding, cutting, or the like, and forming the through-hole grooves 16 and the through-hole inlets 15 in the outer peripheral side portion thereof. Here, fig. 3 is a schematic view showing a state in which a part of an outer peripheral side wall of a medical honeycomb structure according to another example of the present invention is removed. Through-hole grooves 16 of various lengths are formed, and through-hole inlets 15 are formed adjacent to the through-hole grooves 16. For example, as shown in fig. 4, an inclined surface is formed on the outer peripheral side portion by cutting or the like at an angle, and the through-hole groove 16 and the through-hole entrance 15 are formed at the same time. By providing such an inclined surface, not only the through-hole grooves and the through-hole entrances can be formed in the outermost layer of the honeycomb structure, but also the through-hole grooves and the through-hole entrances can be formed in a plurality of layers further inside together with the outermost layer.

The inclined surface formed in the outer peripheral portion of the medical honeycomb structure of the present invention is a surface inclined with respect to the penetrating direction of the through-holes, and a plurality of inclined surfaces may be formed in a step shape. As the inclination angle, an angle that can form the through-hole groove and the through-hole entrance is used, and as such a condition, for example, a tangent of an angle formed by the inclined surface and the through-hole direction is a value larger than a value obtained by dividing a thickness of the outer peripheral side wall or the partition wall by a length of the honeycomb structure in the through-hole direction.

In the present invention, the thickness of the outer peripheral side wall means: in the honeycomb structure 14 shown in fig. 1, a portion obtained by removing a plurality of through holes 11 extending in one direction and partition walls 12 dividing the through holes, that is, an outer peripheral side wall 13 surrounded by a honeycomb structure portion formed by the through holes, is thick. When the thickness of the outer peripheral side wall is not uniform, the thickness of the thickest portion is defined as the thickness of the outer peripheral side wall.

In the present invention, the thickness of the partition walls means: in the honeycomb structure 14 shown in fig. 1, the through-holes are divided into the thicknesses of the partition walls 12. When the thickness of the partition wall is not uniform, the thickness of the partition wall dividing the adjacent through holes is the smallest thickness.

Further, although it is preferable to provide the inclined surface on the outer peripheral side portion, it is not always necessary to provide the inclined surface, and for example, when the 1 st surface and the 2 nd surface which are parallel to the penetrating direction of the through holes are formed on a part of the outer peripheral side portion, the 1 st surface and the 2 nd surface may be formed so that the difference between the distances from the 1 st surface and the 2 nd surface to the center portion of the honeycomb structure becomes a value larger than the thickness of the partition walls, thereby forming the through hole grooves and the through hole inlets.

The thickness of the outer peripheral side wall is preferably 300 μm or less, more preferably 200 μm or less, and further preferably 150 μm or less as it is thinner within a range in which molding such as extrusion molding is possible.

In the medical honeycomb structure of the present invention, from the viewpoint of facilitating the penetration of the tissue from the periphery of the honeycomb structure into the tissue inside the honeycomb structure, the ratio of the uneven surface (the surface of the portion subjected to polishing or cutting) on the outer peripheral side surface on which the through-hole grooves and the through-hole inlets are formed is preferably 10% or more, more preferably 50% or more, further preferably 80% or more, particularly preferably 95% or more, and most preferably 100% of the area of the outer peripheral side surface.

< entrance of through-hole >

In a typical honeycomb structure obtained by extrusion molding, as shown in fig. 1, the outer peripheral side portion is covered with a smooth outer peripheral side wall 13, but in the present invention, at least a part of the outer peripheral side wall is removed to expose the through-holes (honeycomb structure portions) inside at the outer peripheral side surface. In the present invention, the end portion inlet of the through hole exposed at the outer peripheral side surface is referred to as a through hole inlet. The through-hole entrance is an end entrance of the through-hole exposed on the outer peripheral side surface, and is separated from the through-hole end entrance existing on the C-plane from the beginning (even if the outer peripheral side wall is not removed).

< through hole groove >

As in the through-hole entrance, the groove formed by the sidewall of the through-hole is formed by removing at least a part of the outer peripheral sidewall. In the present invention, the groove is referred to as a through hole groove. The side wall of the through hole includes both the outer peripheral side wall and the partition wall. In the present invention, the ratio (groove aspect ratio c/a) of the length in the longitudinal direction (c in fig. 5) to the length in the width direction (a in fig. 5) of the through-hole groove is important for forming an oriented structure on the outer peripheral side portion of the honeycomb structure, and the groove aspect ratio is preferably 1.5 or more, more preferably 2.0 or more, further preferably 3.0 or more, and particularly preferably 4.0 or more. The through-hole groove of the present invention includes a groove having a side portion missing over the entire length of the through-hole (a groove extending over the entire length of the through-hole).

< through-hole inlet and through-hole groove position in medical honeycomb structure of the present invention >

In the case of the honeycomb structure of the present invention, not only the structure enters the inside of the honeycomb structure from the C-plane, but also, for example, the peripheral structure enters the inside of the honeycomb structure from the inlets of the through holes formed in the outer peripheral side portion of the honeycomb structure, and the peripheral structure is joined to the honeycomb structure by the fitting force. Therefore, it is more preferable that the through-hole entrances are formed not only in the outermost layer of the honeycomb structure but also in a plurality of layers such as the 2 nd outer layer, the 3 rd outer layer, and the 4 th outer layer inside the honeycomb structure. That is, as shown in fig. 4, in the case where the through-hole entrances are formed not only in the outermost layer of the honeycomb structure but also in the layer inside, the bonding is ensured by the structure of the penetrated orientation, that is, not only by the structure around the honeycomb structure and the oriented structure penetrating into the through-holes located in the outermost layer of the honeycomb structure but also by the oriented structure penetrating into the through-holes located in the outermost layer of the honeycomb structure, and therefore, the bondability of the structure to the material surface can be further ensured.

Fig. 4 is a schematic view showing a state where a plurality of layers of the outer peripheral side wall of the honeycomb structure of the present invention are removed, where 15-1 is a through-hole inlet located at the outermost layer (farthest portion as viewed from the central through-hole), 15-2 is a through-hole inlet located at the 2 nd outer layer (farthest portion next to 15-1 as viewed from the central through-hole), and 15-3 is a through-hole inlet located at the 3 rd outer layer (farthest portion next to 15-2 as viewed from the central through-hole). In addition, 16-1, 16-2 and 16-3 are through-hole slots continuous with 15-1, 15-2 and 15-3, respectively. Such a configuration can be easily formed by providing an inclined surface on the outer peripheral side portion.

< Presence ratio of through-hole entrance >

In the medical honeycomb structure of the present invention, the larger the number of the through-hole inlets, the better. The preferable number of through-hole entrances depends on the size of the honeycomb structure, and therefore the existence ratio of the through-hole entrances is expressed as the ratio of the number of through-hole entrances of the outermost layer to the number of through-holes. In the present invention, the ratio of the through-hole entrance is preferably 0.05 or more, more preferably 0.1 or more, further preferably 0.4 or more, particularly preferably 0.5 or more, and most preferably 1.0 or more.

In terms of the number of through-hole inlets, a plurality of through-hole inlets can be provided for one through-hole by a method of providing a plurality of inclined surfaces or a plurality of removal surfaces on the outer peripheral portion, which is extremely useful. In this case, the ratio of the through-hole entrance to be present is preferably 1.0 or more, more preferably 1.3 or more, further preferably 1.6 or more, and further preferably 2.0 or more.

< through hole penetrating through side wall (partition wall and peripheral side wall) of through hole >

The honeycomb structure is preferable for imparting orientation to the formed structure, but has a disadvantage that the bonding property between the formed structures is insufficient, except for the case of using a material such as apatite carbonate which is substituted for the structure. Therefore, in order to impart orientation to the formed structure and impart three-dimensional continuity to the formed structure, it is sometimes effective to provide a through-hole penetrating through the side wall (partition wall and outer peripheral side wall) of the through-hole in addition to the through-hole groove and the through-hole inlet in the outer peripheral side portion, and it is particularly preferable to provide the through-hole in the outer peripheral side wall. The through holes penetrating the plurality of side walls (partition walls and outer peripheral side walls) can be formed by, for example, drilling.

< shape of cell cross section (through-hole cross section) in honeycomb structure and diameter of cell (through-hole) >

The honeycomb structure for medical use of the present invention has a polygonal or circular cell cross section.

The diameter of the through-holes in the medical honeycomb structure of the present invention is preferably 5 μm or more and 400 μm or less, more preferably 10 μm or more and 300 μm or less, and still more preferably 20 μm or more and 250 μm or less. The diameter of the through hole means the length of the diameter of a circle when the cross section is a circle, and means the length of a diagonal line when the cross section is a polygon such as a square.

The diameter of the cross section is used to calculate the aspect ratio of the cell (through-hole). The ratio of the length in the longitudinal direction of the through-hole to the diameter (unit aspect ratio) is preferably 3 or more, more preferably 5 or more, and still more preferably 10 or more, from the viewpoint of adhesion of cells and formation of oriented tissue.

< thickness of partition wall of through hole >

The thickness of the partition walls of the through-holes of the medical honeycomb structure of the present invention is a factor that affects the mechanical strength of the honeycomb structure, the speed of replacement of the medical honeycomb structure into a tissue, and the like.

That is, when the thickness of the partition walls is large, the mechanical strength of the medical honeycomb structure becomes large, while when the medical honeycomb structure is composed of carbonate apatite which can be substituted for bone, or the like, the substitution of the medical honeycomb structure into the tissue becomes slow.

In addition, for example, in the case where a calcium carbonate honeycomb structure is immersed in a phosphate aqueous solution and converted into a carbonate apatite honeycomb structure for medical use by a dissolution precipitation type composition conversion reaction, the dissolution precipitation type composition conversion reaction proceeds from the surface of a precursor, and therefore, when the thickness of partition walls is large, there is a problem as follows: if the production is not performed at a high temperature such as hydrothermal reaction or the like without consuming time for the reaction, the production of the carbonate apatite honeycomb structure cannot be performed; and so on. For example, in the case of a carbonate apatite honeycomb structure produced at a high temperature such as hydrothermal conditions, the thickness of partition walls is extremely important because the crystallinity is high and the structural reaction such as bone conductivity is poor as compared with a carbonate apatite honeycomb structure produced at a temperature of 100 ℃.

Since the balance of these is important, the thickness of the partition walls of the through-holes of the medical honeycomb structure is preferably 10 μm or more and 300 μm or less, more preferably 20 μm or more and 200 μm or less, and still more preferably 30 μm or more and 150 μm or less.

In the case where the composition of the medical honeycomb structure of the present invention is apatite carbonate and a medical apatite honeycomb structure having more excellent tissue affinity such as bone conductivity is produced, the thickness of the partition walls is preferably 10 μm or more and 200 μm or less, more preferably 20 μm or more and 150 μm or less, and further preferably 30 μm or more and 100 μm or less.

< ratio of diameter of through-hole to thickness of partition wall >

Not only the thickness of the partition walls of the medical honeycomb structure of the present invention but also the size of the through-holes of the cells are factors that affect the mechanical strength of the honeycomb structure, the speed of replacement of the medical honeycomb structure into a tissue, and the like.

When the ratio of the diameter of the through-hole (diameter in the cross section of the through-hole) to the thickness of the partition walls is large, the porosity of the medical honeycomb structure becomes large, cells and tissues easily enter the inside, and the mechanical strength of the medical honeycomb structure becomes small. In view of their balance, the ratio of the diameter of the through-holes of the honeycomb structure to the thickness of the partition walls is preferably 0.2 or more and 20 or less, more preferably 0.25 or more and 10 or less, and still more preferably 0.5 or more and 5 or less.

< size (volume) > < honeycomb structure

The size of the outer shape of the medical honeycomb structure (block) of the present invention is preferably 10^-8m³Above and 10^-3m³Hereinafter, more preferably 7 × 10^-5m³Above and 4 × 10^-4m³The following.

The size of the outer shape of the medical honeycomb structure of the present invention is obtained by measuring the length of the honeycomb structure and calculating the length. For example, when the honeycomb structure is cylindrical, the length of the diameter of the C-plane as a circle and the length of the C-plane in the direction of the through-hole are measured and calculated from both. In this case, the apparent density of the honeycomb structure can be determined by measuring the weight of the honeycomb structure and dividing the weight by the volume. This makes it possible to calculate the volume from the weight of the crushed product (particles) of the honeycomb structure.

Broken article (particle) of honeycomb structure

The crushed product of the medical honeycomb structure of the present invention is obtained by crushing the massive medical honeycomb structure. The size (shape) of the crushed material is preferably 10^-12m³Above and less than 10^-8m³More preferably 4X 10^-12m³Above and less than 10^-8m³More preferably 6X 10^-12m³Above and less than 10^-8m³。

As described above, the size (outer shape) of the crushed honeycomb structure (pellet) can be determined by dividing the weight of the crushed honeycomb structure (pellet) by the apparent density of the uncrushed honeycomb structure used for the production of the crushed honeycomb structure (pellet).

< composition >

The composition (material) of the medical honeycomb structure is not particularly limited, and preferably contains at least a calcium compound having excellent cell affinity and tissue affinity. The mechanism of the preferred calcium-containing compound as the composition of the medical honeycomb structure has not been sufficiently clarified, but it is considered that the composition is preferred to be a calcium-containing compound because calcium plays an important role in cell adhesion.

In the present invention, among the calcium compounds, at least one selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate and calcium-containing glass is preferable. Calcium phosphate is preferably calcium carbonate or calcium sulfate because it contains a phosphate component in addition to calcium and the phosphate component plays an important role in cell adhesion and the like, and calcium carbonate or calcium sulfate exhibits solubility suitable for supplying calcium to cells.

The calcium phosphate in the present invention refers to a salt of phosphoric acid and calcium, and examples thereof include calcium orthophosphate, calcium metaphosphate, condensed calcium phosphate and the like. Among calcium phosphates, calcium orthophosphate is preferred because it exhibits superior osteoconductivity and tissue affinity. The calcium orthophosphate in the present invention refers to a salt of calcium orthophosphate and calcium, and examples thereof include tetracalcium phosphate, apatite (including hydroxyapatite and carbonic apatite), α -tricalcium phosphate, β -tricalcium phosphate, octacalcium phosphate, and the like.

Among the calcium phosphates, at least one selected from the group consisting of apatite such as apatite carbonate, β -tricalcium phosphate (β -TCP), α -tricalcium phosphate, and octacalcium phosphate is more preferable.

The carbonate apatite in the present invention means apatite in which part or all of phosphoric acid groups and hydroxyl groups of the apatite are substituted by carbonate groups. Apatite having hydroxyl groups substituted with carbonate groups is called A-type carbonate apatite, apatite having phosphate groups substituted with carbonate groups is called B-type carbonate apatite, and apatite having both carbonate groups substituted with carbonate groups is called AB-type carbonate apatite. In addition, Na, K and the like are often contained in the crystal structure along with substitution of the phosphate group by a carbonate group, and a compound obtained by substituting a part of the carbonate apatite by another element or a void is also included in the carbonate apatite of the present invention.

The honeycomb structure made of the carbonate apatite has an advantage that a structure having a large size can be manufactured.

For example, in a method for producing a medical bone filler mainly composed of apatite carbonate disclosed in japanese patent No. 4854300, a calcium carbonate block as a precursor is immersed in a phosphate aqueous solution to produce apatite carbonate. The reaction is a dissolution precipitation reaction in which calcium carbonate as a precursor is dissolved in an aqueous solution to make Ca²⁺And CO₃ ^2-Free in aqueous solution. Ca in the presence of phosphate in aqueous solution²⁺、CO₃ ^2-And PO₄ ^3-The aqueous solution in which the three components coexist becomes supersaturated with respect to the apatite carbonate, and precipitates on the surface of the precursor. Thus, calcium carbonate as a precursor is converted into carbonate apatite in its composition by the dissolution-precipitation reaction while maintaining the basic composition. Since the dissolution and precipitation reaction proceeds from the surface of the precursor toward the inside, the reaction time significantly increases as the depth from the surface of the precursor increases in the case where the precursor is a dense body.

Even when the apparent size of the whole body of the porous body such as foam disclosed in japanese patent No. 4854300 is large, the phosphate aqueous solution enters the inside of the porous body and the dissolution and precipitation reaction starts from the inner surface of the porous body, and therefore the composition conversion by the dissolution and precipitation reaction is completed in a relatively short time.

As is clear from the reaction mechanism, Ca was precipitated in the reaction²⁺、CO₃ ^2-And PO₄ ^3-The three must coexist on the surface of the material. Ca dissolved from the surface of the material when the calcium carbonate block is a dense body²⁺And CO₃ ^2-Since the metal particles are diffused and disappear from the surface of the material, the precipitation reaction is less likely to occur. On the other hand, since the foam or the like is porous, Ca eluted from the surface of the transverse webs of the foam is more likely than in the case of a block-like foam having no interconnected pores²⁺And CO₃ ^2-The disappearance from the material surface due to diffusion is reduced.

When the porous body has a honeycomb structure, since the honeycomb is a porous body having through holes in the uniaxial direction, Ca eluted from the honeycomb partition walls²⁺And CO₃ ^2-The disappearance from the surface of the material due to diffusion is very limited. Therefore, if the honeycomb-structured precursor is used, a large-sized apatite carbonate can be produced.

The apatite in the present invention means a substance having A₁₀(BO₄)₆C₂As the compound having a basic structure, Ca is mentioned as A² ⁺、Cd²⁺、Sr²⁺、Ba²⁺、Pb²⁺、Zn²⁺、Mg²⁺、Mn²⁺、Fe²⁺、Ra²⁺、H⁺、H₃O⁺、Na⁺、K⁺、AL³⁺、Y³⁺、Ce³⁺、Nd³⁺、La³⁺、C⁴ ⁺Void, etc. as BO₄Can cite PO₄ ^3-、CO₃ ^2-、CrO₄ ^3-、AsO₄ ^3-、VO₄ ^3-、UO₄ ^3-、SO₄ ^2-、SiO₄ ^4-、GeO₄ ^4-And voids, and the like, and examples of C include OH^-、OD^-、F^-、Br^-、BO^2-、CO₃ ^2-、O^2-Voids, etc.

In addition, A is₁₀(BO₄)₆C₂Is the basic structural formula of apatite, Ca₁₀(PO₄)₆(OH)₂The basic structural formula of the calcium phosphate apatite is described, but the apatite of the present invention is not limited to the basic structural formula. For example, in the case of calcium phosphate apatite, Ca is deficient in apatite Ca_10-x(HPO₄)_x(PO₄)_6-x(OH)_2-xCarbonate apatite, substituted apatite, etc. are known, and these are included in the apatite of the present invention.

Tricalcium phosphate in the present invention means Ca₃(PO₄)₂Calcium phosphate compounds having a typical composition include compounds in which calcium is partially substituted with other metal ions such as sodiumIncluding things. Among tricalcium phosphates, there are α 'type tricalcium phosphate, α type tricalcium phosphate, and β type tricalcium phosphate, which are stable at high temperatures, and in the present invention, α' type tricalcium phosphate and α type tricalcium phosphate are referred to as α type tricalcium phosphate.

Although the compositions of α -tricalcium phosphate and β -tricalcium phosphate are the same, the solubilities are greatly different, and the behaviors in the living body are completely different. β -tricalcium phosphate has low solubility and is clinically used as a bone substitute material, and therefore β -tricalcium phosphate is generally preferred to α -tricalcium phosphate. On the other hand, α -tricalcium phosphate has a high solubility and is used as a component of bioactive cement. However, when the bone defect is not so large and the porous body is formed, it is sometimes preferable to use α -type tricalcium phosphate as the core rather than β -type tricalcium phosphate.

The octacalcium phosphate of the present invention is also called octacalcium phosphate or octacalcium phosphate, and is Ca₈H₂(PO₄)₆·5H₂O is calcium phosphate of representative composition.

The calcium carbonate in the present invention is CaCO₃Is one of the calcium components of the basic composition. In addition, calcium carbonate of the present invention includes compounds in which a part of Ca is substituted with another element such as Mg.

The term "calcium sulfate" as used herein means CaSO₄Hemihydrate and dihydrate, which are one of the basic calcium components, are also known, and these hydrates are also included in the calcium sulfate of the present invention.

The calcium-containing glass of the present invention is one of calcium components, and is a glass or glass ceramic containing calcium. The glass component containing calcium can be produced by a known method by melting and quenching the glass component. The calcium-containing crystallized glass obtained by pulverizing, firing and crystallizing calcium-containing glass is also included in the calcium-containing glass of the present invention. For example, Na called Bioglass (registered trademark) can be mentioned₂O-CaO-SiO₂-P₂O₅Is glass (representative composition is Na)₂24.5% by mass of O, 24.5% by mass of CaO, and SiO₂45 mass% of P₂O₅6% by mass), and crystallized glass called Cerabine (registered trademark) A-W (typical composition is MgO 4.6% by mass, CaO 44.7% by mass, SiO₂34.0 mass% of P₂O₅16.2 mass% of CaF₂0.5 mass%), and the like. These calcareous glasses can be produced by known methods.

The polymer material in the present invention means an organic material having a molecular weight exceeding 10000. Specifically, examples of the polymer material include biopolymers such as collagen, gelatin, chitin, and chitosan, absorbent polymers such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and polycaprolactone, polyether ether ketone (PEEK), polyether ketone (PEK), polyether ether ketone (PEEKK), polyether ketone ester, polyimide, polysulfone, polyethylene, polypropylene, and polyethylene terephthalate. The polymer material may be used alone or in combination of two or more. In particular, by mixing the calcium compound or the like with a polymer material, a medical honeycomb structure having flexibility can be produced. That is, when flexibility is to be imparted to the medical honeycomb structure, a polymer material is present in the composition without performing high-heat treatment such as degreasing treatment described later.

< method for manufacturing honeycomb Structure >

The method for manufacturing a medical honeycomb structure according to the present invention includes the steps of: a structure-with-outer-wall manufacturing step of extruding a material through a honeycomb structure forming die to manufacture a honeycomb structure having an outer peripheral side wall; and an outer peripheral side portion processing step of removing the outer peripheral side wall of the honeycomb structure having the outer peripheral side wall and forming the through-hole groove and the through-hole inlet at the outer peripheral portion, preferably having a degreasing step. Further, other steps such as a firing step may be provided. The degreasing step and the firing step may be performed simultaneously.

Specifically, in order to produce the medical honeycomb structure of the present invention made of hydroxyapatite, for example, first, a hydroxyapatite powder and an organic binder are mixed, and extrusion molding is performed by a method disclosed in japanese patent No. 3405536, japanese patent application laid-open No. 10-59784, or the like, to produce a honeycomb structure having an outer peripheral side wall as shown in fig. 1 and having a composition of hydroxyapatite and an organic binder (a structure producing step with an outer wall). Next, the machining (outer peripheral side portion machining step) is performed as follows: at least a part of the outer peripheral side wall of the honeycomb structure having the outer peripheral side wall is removed by polishing, cutting, or the like, and through-hole grooves and through-hole inlets are formed in the outer peripheral portion. The removal of the outer peripheral side wall may be performed after the degreasing step, but in general, workability is good when the removal is performed before the degreasing step. Here, degreasing means removing the organic binder. For example, it means that the organic binder is removed from a structure having a honeycomb structure made of hydroxyapatite powder and the organic binder. The degreasing may be performed by a conventional general method, and for example, the degreasing may be performed by heating and burning an organic binder. After the degreasing step, firing may be performed as necessary. Through these steps, the medical honeycomb structure of the present invention made of hydroxyapatite can be produced.

The organic binder is used to impart the desired viscosity to the ceramic powder particles for extrusion. As the organic binder, known binders such as wax-based binders and acrylic binders can be used without limitation.

In the case of manufacturing a honeycomb structure composed of only ceramics, degreasing is required, but in the case of manufacturing a honeycomb structure composed of ceramics and polymers with flexibility as a priority, a degreasing step is not required.

The hydroxyapatite honeycomb structure is stable even at high temperatures, and is fired at high temperatures of 800 to 1300 ℃ without decomposition, so that the honeycomb structure can be easily produced.

On the other hand, in the case of a carbonate apatite honeycomb structure having excellent cell adhesion and tissue adhesion, thermal decomposition occurs due to high-temperature firing, or cell adhesion and tissue adhesion are reduced, and therefore, as an effective production method, the following method can be exemplified: honeycomb structures (precursors) having different compositions are produced, and the composition is converted into apatite carbonate by a dissolution precipitation type composition conversion reaction while maintaining the macroscopic form of the honeycomb structure.

Among the calcium carbonate honeycomb structure, calcium sulfate honeycomb structure, α -tricalcium phosphate honeycomb structure, and the like are effective as precursors having different compositions of the carbonate apatite honeycomb structure from the viewpoint of solubility, and among these, calcium carbonate honeycomb is particularly suitable as a precursor because only carbonate apatite exists as a stable phase as compared with calcium carbonate when immersed in a phosphate aqueous solution.

However, calcium carbonate is insufficient in sinterability and thermally decomposes at high temperatures, and therefore a method using calcium hydroxide is useful.

That is, the following method is preferable, and the method has the steps of: a structure-with-outer-wall manufacturing step of extruding a mixture in which calcium hydroxide and an organic binder are mixed through a honeycomb structure-forming die to manufacture a honeycomb structure having an outer peripheral side wall; a degreasing step of degreasing the honeycomb structure; a carbonation step of carbonating the honeycomb structure simultaneously with or after the degreasing step; and a phosphorization step of applying a phosphate aqueous solution to the honeycomb structure having undergone the carbonation step, and including an outer peripheral side portion processing step of removing at least a portion of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall to form through-hole grooves and through-hole inlets in the outer peripheral portion, at any stage after the outer wall-equipped structure production step. The outer peripheral side portion processing step may be performed at any stage of before and after the degreasing step, before and after the carbonation step, and before and after the apatite step.

In order to carbonate the honeycomb structure in the degreasing process, it is preferable to perform degreasing under the condition that carbon dioxide coexists with oxygen when heating the honeycomb structure. Oxygen is necessary for degreasing, i.e. incinerating, the binder. In theory, degreasing occurs in the presence of oxygen, but when the oxygen partial pressure is low, degreasing is difficult, and therefore, the volume percentage of oxygen in the environment in which the honeycomb structure is degreased is preferably 10% or more, more preferably 20% or more, and further preferably 30% or more.

On the other hand, carbon dioxide is necessary in order to carbonate calcium hydroxide. The organic binder (polymer material) contains carbon, and carbon dioxide is generated by degreasing the organic binder, so that carbon dioxide does not necessarily need to be supplied. However, carbon dioxide is not present after degreasing, and under such an environment, calcium carbonate is easily thermally decomposed. Therefore, the volume percentage of carbon dioxide in the environment in which the honeycomb structure is degreased is preferably 10% or more, more preferably 20% or more, and still more preferably 30% or more.

The degreasing temperature varies depending on the volume percentages of oxygen and carbon dioxide in the environment in which the honeycomb is degreased, what degree of whiteness is required for the produced calcium carbonate honeycomb structure, and the like, and is preferably 400 ℃ to 900 ℃, more preferably 450 ℃ to 800 ℃, and still more preferably 500 ℃ to 700 ℃.

In the case of producing calcium carbonate honeycombs by carbonation treatment simultaneously with degreasing, although the number of steps is small and it is economical, carbonation may be performed after degreasing. When it is difficult to supply oxygen and carbon dioxide at the same time, high-temperature degreasing is performed only under oxygen, or when it is also difficult to supply oxygen, high-temperature degreasing is performed in the atmosphere. In this process, calcium carbonate, or calcium hydroxide, or both, are thermally decomposed to form calcium oxide. The presence of calcium oxide in the honeycomb structure causes digestion, and when immersed in water, the honeycomb structure is not able to retain its form and disintegrates, or the honeycomb structure has low mechanical strength. Therefore, in the case where calcium oxide is formed, the carbonation treatment is performed again. The carbonation treatment is performed by contacting the honeycomb structure with carbon dioxide. In the case of the dry type, the honeycomb structure is contacted with carbon dioxide at a temperature of 920 ℃ (thermal decomposition of calcium carbonate) or less. In the wet type, the honeycomb structure is brought into contact with carbon dioxide at a humidity of 50% or more.

Next, the produced calcium carbonate honeycomb is immersed in a phosphate aqueous solution, and the composition thereof is converted into carbonate apatite by a dissolution precipitation type composition conversion reaction while maintaining the honeycomb structure, thereby producing a carbonate apatite honeycomb structure. The dipping treatment is preferable, but a treatment of continuously spraying or the like may be used.

A method for producing a carbonic acid apatite honeycomb structure using a calcium sulfate honeycomb structure as a precursor is also useful. Since calcium sulfate is thermally stable, it can be produced by the same method as the method for producing a hydroxyapatite honeycomb structure.

That is, there can be mentioned a method comprising the steps of: a structure body manufacturing step of manufacturing a honeycomb structure body having an outer peripheral side wall by extruding a mixture in which calcium sulfate and an organic binder are mixed through a honeycomb structure forming die; a degreasing step of degreasing the honeycomb structure; and a apatite step of applying an aqueous solution containing carbonate and phosphate or sequentially applying an aqueous solution containing carbonate and an aqueous solution containing phosphate to the honeycomb structure subjected to the degreasing step, and further comprising an outer peripheral side portion processing step of removing at least a part of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall and forming a through-hole groove and a through-hole inlet in the outer peripheral side portion at any stage after the outer wall-provided structure production step. The degreasing process may be performed before or after the outer peripheral side portion processing process. The outer peripheral side portion processing step may be performed at any stage of before and after the degreasing step and before and after the apatite step.

Specifically, a calcium sulfate powder and an organic binder are mixed and extruded by a method disclosed in japanese patent No. 3405536 and japanese patent application laid-open No. 10-59784 to produce a honeycomb structure having an outer peripheral side wall as shown in fig. 1, which has a composition of calcium sulfate and an organic binder (a structure producing step with an outer wall).

Next, the binder is degreased, i.e., incinerated and removed, by a known degreasing step.

The calcium sulfate honeycomb structure is immersed in an aqueous solution containing both phosphate and carbonate, for example, and the composition is converted into carbonate apatite by a dissolution-precipitation type composition conversion reaction while maintaining the honeycomb structure, thereby producing a carbonate apatite honeycomb structure. Although this production method is simple, sulfate groups may be detected as the composition of the carbonate apatite honeycomb structure. The reason is presumed to be: since the honeycomb structure exhibits a cell structure, the diffusion of the solution inside the cell structure is limited.

Therefore, the following production method may be more preferable: the calcium carbonate honeycomb structure is produced by immersing a calcium sulfate honeycomb structure in a solution containing carbonate, converting the composition of the calcium sulfate honeycomb structure into calcium carbonate by a dissolution precipitation type composition conversion reaction while maintaining the honeycomb structure, and then, by immersing a calcium carbonate honeycomb structure in a solution containing phosphate, converting the composition of the calcium carbonate honeycomb structure into apatite carbonate by a dissolution precipitation type composition conversion reaction while maintaining the honeycomb structure.

< method for producing crushed article of honeycomb structure >

The method for producing a crushed product of a medical honeycomb structure of the present invention is characterized by comprising the steps of: a structure body manufacturing step of manufacturing a honeycomb structure body having an outer peripheral side wall by extruding a material through a honeycomb structure forming die; an outer peripheral side portion processing step of removing at least a part of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall to form a through-hole groove and a through-hole entrance in the outer peripheral side portion; and a crushing step of crushing the honeycomb structure having the through-hole grooves and the through-hole inlets into 10 pieces^-12m³Above and less than 10^-8m³The above production method may further comprise a degreasing step, a firing step, and the like.

In the case of a ceramic honeycomb structure, the honeycomb structure produced after the degreasing step and after the firing step is brittle, and it is difficult to produce desired particles by crushing, or the yield is low. Therefore, it is preferable to perform crushing before the degreasing step. The crushing can be performed by using a known crusher or pulverizer such as a cutting mill. After the crushing, the crushed material is classified by using a sieve or the like as necessary to produce a crushed product of the honeycomb structure having a desired size.

[2 nd medical honeycomb structure of the present invention ]

The 2 nd medical honeycomb structure of the present invention is a medical honeycomb structure including a plurality of through holes extending in a single direction, and is characterized in that the medical honeycomb structure is composed of a composition containing a carbonic acid apatite. That is, both the structure with the outer peripheral side wall removed (for example, the structure shown in fig. 2) and the structure without the outer peripheral side wall removed (for example, the structure shown in fig. 1) such as the medical honeycomb structure described above are included. The explanation of each configuration can be directly applied to the explanation of the medical honeycomb structure described above.

The crushed product of the 2 nd medical honeycomb structure according to the present invention is obtained by crushing the 2 nd medical honeycomb structure. The explanation of each component can be applied as it is to the explanation of the crushed material of the medical honeycomb structure described above.

As a method for producing the above-described 2 nd medical honeycomb structure of the present invention, there can be mentioned: the above-described production method itself (outer peripheral side wall removed) of the medical honeycomb structure of the present invention comprising carbonic acid apatite in the composition; a method (having an outer peripheral side wall) in which the outer peripheral side portion processing step is not performed.

Specifically, as a method for manufacturing the honeycomb structure for medical use of the 2 nd embodiment,

the following method is exemplified, which comprises the steps of: a structure-with-outer-wall manufacturing step of extruding a mixture in which calcium hydroxide and an organic binder are mixed through a honeycomb structure-forming die to manufacture a honeycomb structure having an outer peripheral side wall; a degreasing step of degreasing the honeycomb structure; a carbonation step of carbonating the honeycomb structure simultaneously with or after the degreasing step; and a phosphorization step of applying a phosphate aqueous solution to the honeycomb structure subjected to the carbonation step,

further, there is provided a method comprising the steps of: a structure-with-outer-wall manufacturing step of extruding a mixture in which calcium sulfate and an organic binder are mixed, through a honeycomb structure formation die, to manufacture a honeycomb structure having an outer peripheral side wall; a degreasing step of degreasing the honeycomb structure; and a apatite step of applying an aqueous solution containing carbonate and phosphate to the honeycomb structure subjected to the degreasing step, or applying an aqueous solution containing carbonate and an aqueous solution containing phosphate to the honeycomb structure in this order.

[ Effect of the medical Honeycomb Structure of the invention ]

The medical honeycomb structure of the present invention is a structure that satisfies the following requirements expected for medical materials: (1) excellent adhesion or bondability of cells or tissues to the surface of a material; (2) tissue capable of regenerating and reconstructing orientation; (3) the mechanical strength is excellent; (4) in the case of use as a tissue substitute material, is quickly substituted for a desired tissue; (5) can be manufactured at low cost. The mechanism of the medical honeycomb structure of the present invention that satisfies such a requirement can be considered as follows.

< (1) Excellent adhesion or adhesion of cells or tissues to the surface of a material

When a medical material is implanted in a living body, it is often required to be bonded to a peripheral tissue. The surface (surface C in fig. 1) of the honeycomb structure including the through-hole end portions has an open structure and thus has no problem, but generally, the outer peripheral side surface (surface a in fig. 1) has an outer peripheral side wall and is difficult to bond to the surrounding structure. In the honeycomb structure of the present invention, the through-hole grooves and the through-hole inlets that open in the through-hole direction are formed in the a-plane. Therefore, for example, bone tissue enters the honeycomb structure from this site, and the surrounding bone is firmly bonded to the honeycomb structure.

In the case where the composition of the honeycomb structure contains apatite carbonate, since apatite carbonate is absorbed by osteoclast and the like, even when the original apatite carbonate honeycomb structure has a peripheral side wall, osteoclast absorbs the a plane, and as a result, a through-hole entrance opening in the through-hole direction is formed, for example, bone tissue enters the honeycomb structure from the part, and the peripheral bone is firmly bonded to the honeycomb structure. That is, when the apatite carbonate is contained, it is not necessary to provide the through-hole groove and the through-hole inlet in the outer peripheral side portion.

The medical honeycomb structure having through-hole grooves and through-hole entrances in the outer peripheral side portion and having a composition containing apatite carbonate is extremely excellent in bondability to surrounding bones and the like.

< (2) tissue capable of regenerating and reconstructing orientation

Formation of oriented tissue is important from the viewpoint of the functionality of regenerated and reconstructed tissue. As reported in non-patent document 1, tissues such as bone are variously oriented depending on the site. However, as disclosed in non-patent documents 2 and 3, etc., the regenerated bone lacks in orientation and functionality, and therefore, it is necessary to induce orientation.

The honeycomb structure of the present invention has an orientation-linked porous body inside, and since the structure is regenerated and reconstructed along the surfaces of the through-holes of the honeycomb structure, the induction of the structure orientation can be satisfactorily performed. Further, since the honeycomb structure of the present invention also has through-hole grooves and through-hole inlets that open in the through-hole direction in the outer peripheral portion, tissue regeneration and reconstruction are performed along these through-hole grooves, and therefore, tissue orientation can be satisfactorily induced.

When the composition of the honeycomb structure contains apatite carbonate, the apatite carbonate is absorbed by osteoclasts and the like, and therefore, even when the original apatite carbonate honeycomb structure has a peripheral side wall, the osteoclasts absorb the a-plane, and as a result, the through-hole inlets that are open in the through-hole direction are formed, and the tissue orientation can be satisfactorily induced. That is, when the apatite carbonate is contained, it is not necessary to provide the through-hole groove and the through-hole inlet in the outer peripheral side portion.

The medical honeycomb structure having the through-hole grooves and the through-hole inlets at the outer peripheral side and containing the apatite carbonate in the composition is a honeycomb structure having an extremely excellent orientation structure formed on the outer peripheral side.

< (3) Excellent mechanical Strength

It is essential that the medical material function without being damaged at a site where the medical material is implanted. The medical honeycomb structure of the present invention has a honeycomb structure and is superior in mechanical strength to other porous materials, and therefore satisfies this requirement. The mechanical strength of the honeycomb structure is generally evaluated by measuring the compressive strength in the cell direction and the direction perpendicular to the cell, and the mechanical strength of another porous body having the same porosity or more is exhibited by using the honeycomb structure.

< (4) in the case of use as a tissue substitute material, is rapidly substituted for the desired tissue

Depending on the composition of the medical material, the material is replaced with tissue. From this viewpoint, carbonate apatite, tricalcium phosphate, calcium sulfate, and calcium carbonate are excellent materials, and among these, carbonate apatite and tricalcium phosphate are more excellent materials, and carbonate apatite is a more excellent material. The material is replaced by tissue through the cells. For example, in the case of carbonate apatite, the osteoclast-resorbing material is replaced with tissue by the same mechanism as bone remodeling in which bone is formed by osteoblasts. Therefore, it is considered that not only the components but also cells are required to be able to invade the inside of the material and the specific surface area is required to be large. In this respect, the medical honeycomb structure of the present invention can use the above-described ideal material, and in addition, cells can invade into the inside of the cell showing connectivity, and the specific surface area is extremely large.

< (5) can be produced at low cost

The honeycomb structure of the present invention can be produced by the following extremely simple production method: the honeycomb forming die is simply passed through, the material is extruded to remove the outer peripheral side wall, or the honeycomb forming die is degreased or dipped in an aqueous solution as necessary. This makes it possible to produce the medical honeycomb structure of the present invention at low cost.

Examples

The present invention will be described in further detail below with reference to examples, but the scope of the present invention is not limited to the examples.

Example 1 Honeycomb Structure (Block) made of calcium carbonate

< Process for producing Structure with outer wall >

Calcium hydroxide powder produced by Nacalai Tesque, K.K. was pulverized into an average particle size of 1 μm with a jet mill, and calcium hydroxide and a wax-based binder produced by Kogyo Seiko were mixed in a weight ratio of 75: 25 are mixed. Then, the honeycomb molding die was attached to a Labo Plastomill manufactured by toyoyo seiko co. As a result of the extrusion molding, a cylindrical binder-containing calcium hydroxide honeycomb structure having a composition of a mixture of calcium hydroxide and a binder and having an outer peripheral side wall was produced as an intermediate. Fig. 6 shows a photograph of the produced columnar calcium hydroxide honeycomb structure containing a binder and having an outer peripheral side wall.

< peripheral side part working procedure >

Next, the outer peripheral side wall of the cylindrical binder-containing calcium hydroxide honeycomb structure was removed by an electric planer, and a through-hole groove (which continues to the through-hole entrance) having a through-hole entrance and a groove aspect ratio of 1.5 or more was formed at the outer peripheral side portion. The photograph is shown in FIG. 7.

< degreasing Process >

Next, the calcium hydroxide honeycomb structure containing the binder was degreased at 700 ℃ under a gas flow containing 50% of carbon dioxide and oxygen. The composition of the honeycomb structure after degreasing was analyzed using a D8ADVANCE type X-ray powder diffraction apparatus manufactured by BRUKER under conditions of an output of 40kV and 40mA and an X-ray source of CuK α (λ ═ 0.15418nm), and it was found to be calcium carbonate.

An electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step (honeycomb structure according to example 1 a) is shown in fig. 8. It was confirmed that: the cells were held after degreasing, and a cylindrical calcium carbonate honeycomb structural block having no outer peripheral side wall and having a through-hole inlet formed in the outer peripheral portion was produced. In addition, it was confirmed that: the groove is provided with a through hole, and the length-width ratio of the groove is more than 30. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole was 210 μm, the thickness of the partition wall was 150 μm, and the length of the through hole was 30 mm. In addition, the volume of the honeycomb structure produced was 2 × 10^-6m³. The ratio of the diameter of the through-hole to the thickness of the partition wall was about 1.4, and the aspect ratio of the through-hole was about 140.

Next, in order to analyze the tissue affinity, the orientation of the regenerated/reconstructed tissue, and the bone replacement of the calcium carbonate honeycomb structural block, the calcium carbonate honeycomb structural body according to example 1b (diameter 7.2mm, height 4.5mm) produced in the same manner as in example 1a was implanted into a bone defect formed in the skull of a japanese white rabbit, and was removed from the surrounding tissue in one piece after 1 month of implantation, and a histopathological examination was performed.

Fig. 9 shows a weakly magnified image of a pathological tissue stained with hematoxylin and eosin. Fig. 9(a) is an image obtained by cutting in a direction perpendicular to through holes (cells) of the honeycomb structure, and fig. 9(b) is an image obtained by cutting in parallel with through holes (cells) of the honeycomb structure.

From the results of the histopathological examination, it was found that the calcium carbonate honeycomb structural body (the outer peripheral side surface was included) was extremely well bonded to the surrounding tissues, and the bone tissue completely penetrated into the calcium carbonate honeycomb structural body. Further, it is known that the regenerated and reconstructed bone tissue is oriented in the longitudinal direction of the cells of the calcium carbonate honeycomb structure particles. In addition, osteoblasts and osteoclasts were observed on the surface of the calcium carbonate honeycomb structure particles. From these circumstances, the calcium carbonate honeycomb blocks were replaced with bone tissue.

Example 2 crushed product (pellet) of honeycomb Structure comprising calcium carbonate

The cylindrical calcium hydroxide honeycomb structure containing a binder prepared in example 1 was crushed by a cutting mill (Fritiz Japan, P-15) equipped with a 2.0mm sieve. Then, the degreasing step was performed under the same conditions as in example 1.

The composition of the honeycomb structure particles after the degreasing step was analyzed by an X-ray powder diffraction apparatus, and calcium carbonate was obtained. Fig. 10 shows an electron micrograph of the produced honeycomb structure particles. It was confirmed that the cells were maintained after degreasing.

Further, the diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 2 mm. Further, the volume of the produced honeycomb structure particles was 9 × 10^-10m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4. An example of the aspect ratio of the through-hole is about 10.

Example 3 Honeycomb Structure (Block) made of calcium carbonate having different cell sizes

A cylindrical calcium carbonate honeycomb structure having no outer peripheral side wall was produced by the same production method as in example 1, except that a mold for honeycomb molding different from that in example 1 was used.

The following were confirmed by an X-ray powder diffraction apparatus: the composition of the honeycomb structure after the degreasing step was calcium carbonate. Fig. 11 shows an electron micrograph after the degreasing step. It was confirmed that: the cells were held after degreasing, and a cylindrical calcium carbonate honeycomb structural block having no outer peripheral side wall and having a through-hole inlet formed in the outer peripheral portion was produced. In addition, it was confirmed that: has through hole slot with length/width ratio of 30 or more. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole was 170 μm, the thickness of the partition wall was 70 μm, and the length of the through hole was 30 mm. In addition, the volume of the honeycomb structure produced was 1.5 × 10^-6m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 2.4, and the aspect ratio of the through hole was about 180.

Example 4 Honeycomb Structure (Block) made of hydroxyapatite

Using hydroxyapatite made of taipingo chemistry instead of the calcium hydroxide powder, a structure body fabrication process with an outer wall and an outer peripheral side portion processing process were performed in the same manner as in example 1.

< degreasing Process >

Next, the hydroxyapatite honeycomb structure containing the binder was degreased in the air and fired at 900 ℃. The composition of the honeycomb structure after degreasing was analyzed using a D8ADVANCE type X-ray powder diffraction apparatus manufactured by BRUKER under conditions that the output was 40kV and 40mA and that K α ray (λ ═ 0.15418nm) of Cu as a characteristic X-ray source, and it was found to be hydroxyapatite.

Fig. 12 shows an electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step. It was confirmed that: the cells were held after degreasing, and a cylindrical hydroxyapatite honeycomb structural block having no outer peripheral side wall and having a through-hole inlet formed in the outer peripheral side portion was produced. In addition, it was confirmed that: the groove is provided with a through hole, and the length-width ratio of the groove is more than 30. In addition, it was confirmed that, in some cases, the through-hole inlet was present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 40 mm. In addition, the volume of the honeycomb structure produced was about 1.1 × 10^-6m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4, and the aspect ratio of the through hole was about 190.

Example 5 crushed Honeycomb Structure (pellet) made of hydroxyapatite

The cylindrical hydroxyapatite honeycomb structure produced in example 4, from which the outer peripheral side portion containing the binder was removed, was pulverized, sieved, and classified into particles that passed through a 1000 μm sieve but did not pass through a 850 μm sieve. The obtained pellets were subjected to a degreasing step under the same conditions as in example 4.

The composition of the honeycomb structure particles after the degreasing step was analyzed by an X-ray powder diffraction apparatus, and the result was hydroxyapatite. It was confirmed that the cells were maintained after degreasing. The diameter of the through-hole was 210 μm, the thickness of the partition wall was 150 μm, and the length of the through-hole was 0.9mm, for example. Further, one volume of the honeycomb structural body particles producedFor example, about 5X 10^-10m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4. An example of the aspect ratio of the through-hole is about 4.

Example 6 Honeycomb Structure (Block) formed from Gypsum (calcium sulfate)

< Process for producing Structure with outer wall >

Hemihydrate gypsum produced by Wako pure chemical industries, Ltd is heated at 1000 ℃ to prepare anhydrite (anhydrous calcium sulfate). Mixing the prepared anhydrous gypsum with a wax binder prepared by Kai Hui Jie Changfeng according to a weight ratio of 80: 20 are mixed. Then, the honeycomb molding die was attached to a Labo Plastomill manufactured by toyoyo seiko co. As a result of the extrusion molding, a columnar anhydrous gypsum honeycomb structure containing a binder and having an outer peripheral side wall and composed of a mixture of anhydrous gypsum and a binder was produced as an intermediate.

< outer wall side part working procedure >

Next, the outer peripheral side wall of the columnar adhesive-containing anhydrite honeycomb structure was removed by an electric planer, and a through-hole groove (which continues to the through-hole entrance) having a through-hole entrance and a groove aspect ratio of 1.5 or more was formed at the outer peripheral side portion.

< degreasing Process >

Next, the anhydrous gypsum honeycomb structure containing the binder was degreased in the air and fired at 1000 ℃. The composition of the honeycomb structure after degreasing was analyzed using a D8ADVANCE type X-ray powder diffraction apparatus manufactured by BRUKER under conditions that the output was 40kV and 40mA and ka radiation (λ ═ 0.15418nm) of Cu as a characteristic X-ray source, and it was found to be anhydrous gypsum.

An electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step is shown in fig. 13. It was confirmed that: the cells were held after degreasing, and a cylindrical anhydrous gypsum honeycomb structural block having no outer peripheral side wall was produced, and a through-hole inlet was formed in the outer peripheral portion. In addition, it was confirmed that: the groove is provided with a through hole, and the length-width ratio of the groove is more than 10. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 21 mm. In addition, the volume of the honeycomb structure produced was about 6 × 10^-7m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4, and the aspect ratio of the through hole was about 100.

Example 7 Honeycomb Structure (Block) made of beta-tricalcium phosphate

< Process for producing Structure with outer wall >

betｃA-tricalcium phosphate powder (betｃA-TCP-A) manufactured by Taiping chemical industry Co., Ltd and ｃA wax binder manufactured by Kyoho corporation were mixed in ｃA weight ratio of 75: 25, mixing is carried out. Then, the honeycomb molding die was attached to a Labo Plastomill manufactured by toyoyo seiko co. As a result of the extrusion molding, a columnar binder-containing β -tricalcium phosphate honeycomb structure having a composition of a mixture of β -tricalcium phosphate and a binder and having an outer peripheral side wall was produced as an intermediate.

< outer wall side part working procedure >

Next, the outer peripheral side wall of the columnar binder-containing β -tricalcium phosphate honeycomb structure was removed by an electric planer, and a through-hole groove having a through-hole entrance and a groove aspect ratio of 1.5 or more (which was continuous with the through-hole entrance) was formed at the outer peripheral side portion.

< degreasing Process >

Next, the binder-containing β -tricalcium phosphate honeycomb structure was degreased in the air and fired at 1050 ℃. The composition of the honeycomb structure after degreasing was analyzed using a D8ADVANCE type X-ray powder diffraction apparatus manufactured by BRUKER under conditions that the output was 40kV and 40mA and that K α ray (λ ═ 0.15418nm) of Cu as a characteristic X-ray source, and as a result, it was known as β type tricalcium phosphate.

Fig. 14 shows an electron micrograph (SEM photograph) of the honeycomb structure after the degreasing step. It was confirmed that: the cells were held after degreasing, and a cylindrical β -tricalcium phosphate honeycomb structural block having no outer peripheral side wall and having a through-hole inlet formed in the outer peripheral side portion was produced. In addition, it was confirmed that: has through hole slot with length/width ratio of 30 or more. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 18 mm. In addition, the volume of the honeycomb structure produced was about 5 × 10^-7m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4, and the aspect ratio of the through hole was about 90.

Example 8 crushed product (pellet) of honeycomb Structure made of beta-tricalcium phosphate

The columnar binder-containing β -tricalcium phosphate honeycomb structure obtained after the outer wall side portion processing step of example 7 was pulverized using a cutter and a mortar. The crushed beta tricalcium phosphate honeycomb structure containing the binder was sieved and classified into particles that passed through a 1000 μm sieve but did not pass through a 850 μm sieve. The obtained pellets were subjected to a degreasing step under the same conditions as in example 7.

The composition of the honeycomb structure particles after the degreasing step was analyzed by an X-ray powder diffraction apparatus, and as a result, β -tricalcium phosphate was obtained. It was confirmed that the cells were maintained after degreasing. The diameter of the through-hole was 210 μm, the thickness of the partition wall was 150 μm, and the length of the through-hole was 0.9mm, for example. In addition, an example of the volume of the honeycomb structure particles to be produced is about 5 × 10^-10m³. The ratio of the diameter of the through-hole to the thickness of the partition wall was about 1.4. An example of the aspect ratio of the through-hole is about 4.

Example 9 Honeycomb Structure (Block) made of alpha-tricalcium phosphate

< composition conversion Process >

The honeycomb structure of β -tricalcium phosphate prepared in example 7 was fired at 1500 ℃ in the atmosphere to convert the composition to α -tricalcium phosphate. The composition of the honeycomb structure after firing was analyzed using a D8ADVANCE type X-ray powder diffraction device manufactured by BRUKER under conditions that the output was 40kV and 40mA and that K α ray (λ ═ 0.15418nm) of Cu as a characteristic X-ray source was used, and as a result, it was known as α -tricalcium phosphate.

Fig. 15 shows an electron micrograph (SEM photograph) of the honeycomb structure after the composition conversion step. It was confirmed that: the cells were held after the composition conversion step, and a columnar α -tricalcium phosphate honeycomb structural block having no outer peripheral side wall and having a through-hole inlet formed in the outer peripheral side portion was produced. In addition, it was confirmed that: the groove is provided with a through hole, and the length-width ratio of the groove is more than 30. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

(example 10) Honeycomb Structure made of Polymer Material

< Process for producing Structure with outer wall >

The honeycomb molding die was attached to a Labo Plastomill manufactured by Toyo Seiki Seisaku-Sho, K.K., and extrusion molding was performed using TAFMER MY-2 as a polyolefin resin manufactured by Mitsui chemical Co.Ltd. As a result of the extrusion molding, a cylindrical TAFMER honeycomb structure having TAFMER as a composition and having an outer peripheral side wall was produced as an intermediate. The obtained TAFMER honeycomb structure had flexibility and could be easily bent by hand.

< outer wall side part working procedure >

Next, the outer peripheral side wall of the columnar TAFMER honeycomb structure having the outer peripheral side wall was removed by a cutter, and a through-hole groove having a through-hole entrance and a groove aspect ratio of 1.5 or more (which is continuous with the through-hole entrance) was formed at the outer peripheral side portion.

Fig. 16 shows an electron micrograph (SEM photograph) of the honeycomb structure from which the outer peripheral side wall was removed. It was confirmed that: the cells were held after the removal of the outer peripheral side walls, and a TAFMER honeycomb structural block having no outer peripheral side walls was produced, and a through-hole inlet was formed in the outer peripheral portion. In addition, it was confirmed that: the groove is provided with a through hole, and the length-width ratio of the groove is more than 30. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole was 210 μm, the thickness of the partition wall was 100 μm, and the length of the through hole was 30 mm. In addition, the volume of the honeycomb structure produced was about 2 × 10^-7m³. The ratio of the diameter of the through-hole to the thickness of the partition wall was about 2.1, and the aspect ratio of the through-hole was about 140.

Example 11 Honeycomb Structure (Block) made of Carbonic apatite

The calcium carbonate honeycomb briquette produced in example 1 was immersed in a 1 molar aqueous solution of disodium hydrogenphosphate at 80 ℃ for 7 days.

The composition of the produced honeycomb structure was analyzed by an X-ray powder diffraction device and a fourier transform infrared spectrophotometer, and as a result, it was apatite carbonate. The content of a carbonic acid group was analyzed by a CHN element analyzer, and as a result, it was 10.8% by weight. An electron micrograph of the produced apatite carbonate honeycomb structure (honeycomb structure according to example 11 a) is shown in fig. 17. It was confirmed that a carbonate apatite honeycomb structural block having no outer peripheral side wall could be produced. It was confirmed that: the cells are held, and a cylindrical calcium carbonate honeycomb structural block having no outer peripheral side wall can be produced, and a through-hole inlet is formed in the outer peripheral side portion. In addition, it was confirmed that: has a through hole groove with a length-width ratio of more than 30. Further, it was confirmed that: in some cases, the through-hole entrance is present not only in the outermost layer but also in the 2 nd outer layer. The outer peripheral side wall removal rate (the ratio of the uneven surface on the outer peripheral side portion on which the through-hole groove and the through-hole entrance are formed) was 100%.

The diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 30 mm. In addition, the volume of the honeycomb structure produced was 2 × 10^-6m³. The ratio of the diameter of the through-hole to the thickness of the partition walls was about 1.4, and the aspect ratio of the through-hole was about 140.

The produced apatite carbonate honeycomb block had a compressive strength in the penetrating direction (c direction in fig. 1) of 90MPa and a compressive strength in the direction perpendicular to the penetrating direction (a direction in fig. 1) of 2 MPa.

Next, in order to analyze the tissue affinity, the orientation of the regenerated/reconstructed tissue, and the bone replacement of the carbonate apatite honeycomb structural block, the carbonate apatite honeycomb (diameter 6mm, height 5mm) according to example 11b, which was produced in the same manner as in example 11a, was embedded in a bone defect portion formed in the femur of a japanese white rabbit, and was removed from the surrounding tissue in one piece after 1 month of embedding, and a histopathological examination was performed.

Fig. 18 shows a weakly magnified image of a pathological tissue stained with hematoxylin and eosin. It was found that the carbonate apatite honeycomb structure block (including the outer peripheral side surface) was extremely well bonded to the surrounding tissue, and the bone tissue completely penetrated into the carbonate apatite honeycomb structure block.

Fig. 19 shows a strongly enlarged image of a pathological tissue of a tissue entering a cell located in a near-center portion of the honeycomb structure from a through-hole entrance that is open in the through-hole direction in an outer peripheral side portion. No inflammatory results were observed. It was found that the formed bone tissue was highly oriented in the longitudinal direction of the cells of the carbonate/apatite honeycomb structural block. Furthermore, many nuclei of osteoclasts and osteoblasts were observed on the surface of the oriented bone formed on the surface of the partition walls of the carbonate apatite honeycomb structural block, and osteocytes were observed inside the formed bone. It is known that, since bone formation inside the honeycomb structure is actively bone-reconstructed, the carbonate apatite honeycomb structure block is replaced with bone tissue. Furthermore, vascular endothelial cells were observed in the cells of the carbonate apatite honeycomb, and erythrocytes were observed in the vascular endothelial cells. From this, it was found that blood vessels were formed inside the carbonate apatite honeycomb. Since the blood vessels were formed and oxygen and nutrients were supplied to the formed bone, it was found that the bone was regenerated to a very high degree by the carbonate apatite honeycomb structure.

Example 12 crushed Honeycomb Structure (pellet) made of Carbonic apatite

The calcium carbonate honeycomb structure particles produced in example 2 were immersed in a 1 molar disodium hydrogenphosphate aqueous solution at 80 ℃ for 7 days. The composition of the honeycomb structure particles was analyzed by an X-ray powder diffraction device and a Fourier transform infrared spectrophotometer, and the result was found to be apatite carbonate. The content of a carbonic acid group was analyzed by a CHN element analyzer, and as a result, it was 10.8% by weight.

An electron micrograph of the produced carbonate apatite honeycomb structure particles is shown in fig. 20. The structure is basically maintained after composition transformation.

The diameter of the through hole is 210 μm, the thickness of the partition wall is 150 μm, and the length of the through hole is 1mm, for example. Further, an example of the volume of the honeycomb structure particles to be produced is 8 × 10^-10m³. The ratio of the diameter of the through hole to the thickness of the partition wall was about 1.4. The aspect ratio of the through-holes was about 5.

Next, in order to analyze the tissue affinity of the particles of the carbonate apatite honeycomb structure, the orientation of the regenerated/reconstructed tissue, and the replacement of the particles into bone, the carbonate apatite honeycomb was implanted into a bone defect formed in the femur of a japanese white rabbit, and was removed from the surrounding tissue in one piece after 1 month of implantation, and a histopathological examination was performed.

Fig. 21 shows a weakly magnified image of a pathological tissue stained with hematoxylin and eosin. It was found that the particles of the carbonate apatite honeycomb structure were extremely well bonded to the surrounding tissue, and the bone tissue completely penetrated into the interior of the particles of the carbonate apatite honeycomb structure.

Fig. 22 shows a strongly enlarged image of a pathological structure of a tissue which enters a cell located in a near-center portion of the honeycomb structure from a through-hole entrance which is open in a through-hole direction in an outer peripheral side portion. It is known that the regenerated and reconstructed bone tissue is oriented in the longitudinal direction of the cells of the carbonate apatite honeycomb structure particles. In addition, osteoclasts were observed on the surface of the particles of the carbonate apatite honeycomb structure. From this, it is known that the particles of the carbonate apatite honeycomb structure are substituted for the bone tissue.

Example 13 Carbonic apatite Honeycomb Block having peripheral side walls

A calcium carbonate honeycomb structure having an outer peripheral side wall was produced as an intermediate in the same manner as in example 1 without processing the outer peripheral side wall, and was immersed in a 1 molar disodium hydrogen phosphate aqueous solution at 80 ℃ for 7 days.

The composition of the honeycomb structural body block was analyzed by an X-ray powder diffraction apparatus and a Fourier transform infrared spectrophotometer, and as a result, it was found to be apatite carbonate. The content of the carbonic acid group was analyzed by a CHN element analyzer, and as a result, it was 10.5% by weight. It was confirmed that: the produced carbonate apatite honeycomb structure can produce a carbonate apatite honeycomb structure block having an outer peripheral side wall while substantially maintaining the structure of the intermediate calcium carbonate honeycomb structure.

Next, in order to analyze the tissue affinity, the orientation of the regenerated/reconstructed tissue, and the bone replacement of the carbonate apatite honeycomb structure block, carbonate apatite honeycombs were implanted into a bone defect formed in the femur of a japanese white rabbit, and the implant was removed from the surrounding tissue in one piece after 1 month, and a histopathological examination was performed.

Therefore, the following steps are carried out: the carbonate apatite honeycomb structure block (including the outer peripheral side wall surface) was bonded extremely well to the surrounding tissue, and the bone tissue completely penetrated into the carbonate apatite honeycomb structure block. Therefore, the following steps are carried out: part of the outer peripheral side wall of the carbonate apatite honeycomb is absorbed, and oriented bone tissue also enters the honeycomb structure from the outer peripheral side wall.

Comparative example 1 hydroxyapatite Honeycomb Block having peripheral side wall

To examine the usefulness of the carbonate apatite honeycomb shown in example 13, a hydroxyapatite honeycomb having the same structure as that of the carbonate apatite structure of example 13 and a hydroxyapatite composition was prepared.

Crushing hydroxyapatite powder into 1 micron of average grain size with a jet mill, mixing the hydroxyapatite powder and a wax binder according to a weight ratio of 75: 25 are mixed. Then, the honeycomb molding die was attached to a Labo Plastomill, and extrusion molding was performed. As a result of the extrusion molding, a cylindrical binder-containing hydroxyapatite powder honeycomb structure having a mixture of hydroxyapatite powder and a binder as a composition and having an outer peripheral side wall was produced as an intermediate.

Next, the binder-containing hydroxyapatite powder honeycomb structure was degreased in air at 700 ℃. Further, the mixture was fired at 1200 ℃ for 6 hours.

The composition of the honeycomb structure after firing was analyzed by an X-ray powder diffraction device of D8ADVANCE type manufactured by BRUKER, and the result was found to be hydroxyapatite.

Next, in order to analyze the tissue affinity, the orientation of the regenerated/reconstructed tissue, and the bone replacement of the hydroxyapatite honeycomb structural block having the outer peripheral wall, a hydroxyapatite honeycomb structure having the outer peripheral wall was implanted into a bone defect portion formed in the femur of a japanese white rabbit, and was removed from the peripheral tissue in one piece after 1 month of implantation, and a histopathological examination was performed.

The surface (surface C in fig. 1) of the hydroxyapatite honeycomb structure having the outer peripheral side wall, which surface is formed by the through-hole end portions, was well bonded to the surrounding structure, but the degree thereof was inferior to that of the carbonate apatite honeycomb of example 13. In addition, the outer peripheral sidewall surface has limited bondability to surrounding tissues. Further, the invasion of the bone tissue into the hydroxyapatite honeycomb structure is limited compared with the invasion of the bone tissue into the interior of the carbonate apatite honeycomb structure block. From this, it is found that the invasion of the bone tissue into the cells of the carbonate apatite honeycomb structure is also superior to that of hydroxyapatite. Further, it is found that, in the case of a honeycomb structure not containing a carbonic apatite, when an outer peripheral side wall is provided, there is a problem in bonding between the peripheral structure and the honeycomb structure.

< test for confirming invasion of bone into through-hole >

Next, the degree of penetration of bone into the through-holes in the carbonate apatite honeycomb and the hydroxyapatite honeycomb was compared.

As shown in example 13 and comparative example 1, when the carbonic apatite having the outer peripheral side wall was compared with the hydroxyapatite, the amount of bone invasion from the surface (surface C in fig. 1) formed by the end of the through-hole was different even though the pore size was the same. Therefore, the degree of bone invasion from the C-plane was confirmed for the carbonate apatite honeycomb having the outer peripheral side wall and the hydroxyapatite honeycomb having the outer peripheral side wall. The results are shown in table 1.

[ Table 1]

It is generally known that the smaller the pore diameter, the less the tissue is infiltrated into the pores. In addition, in order to continue the function of the tissue that has invaded the inside of the stomata, a blood vessel must be formed. As shown in table 1, it is understood that the carbonate apatite honeycomb is more excellent in the penetration of bone from the C-plane than hydroxyapatite at least when the diameter of the through-hole is 280 μm or less. In particular, when the diameter of the through-hole was 70 μm or 170 μm, the invasion of bone into the honeycomb structure was limited or extremely limited when the composition was calcium hydroxide, whereas the invasion of bone from the whole surface of the C-plane into the honeycomb structure was observed for the carbonate apatite. That is, when the diameter of the through-hole is 170 μm or less, a significant effect with hydroxyapatite is observed to be inferior.

In the case of hydroxyapatite, no vascularization was observed even when the maximum through-hole diameter was 280 μm at the fourth stage of embedding. On the other hand, it is known that even if the maximum pore diameter of the carbonate apatite honeycomb is 70 μm, bone tissue invades and vascularization is observed in the bone tissue.

The mechanism of the apatite carbonate honeycomb is not clearly understood, but it is considered that the composition recognition based on cells such as macrophages and the formation of a micro environment based on a honeycomb structure have a synergistic effect.

That is, when embedding a medical material in a living tissue, macrophages recognize the living material as a foreign substance and phagocytose the foreign substance. As a result, part of the carbonate apatite honeycomb and the hydroxyapatite honeycomb is dissolved, and calcium ions and phosphate ions are supplied to the body fluid. Macrophages recognize calcium ions and phosphate ions through a calcium-sensing receptor (CaSR) and the like, and are activated to release cytokines and growth factors. It is considered that since carbonate apatite has the same composition as that of biological bone, has the same ratio of eluted calcium ions and phosphate ions as that of biological bone, and has a solubility in an acidic environment based on a phagocytosis process by macrophages higher than that of hydroxyapatite, it releases a large amount of cytokines and growth factors due to activation of macrophages.

On the other hand, in the case where the carbonate apatite does not hold the through-holes extending in the one direction by the honeycomb structure, for example, in the case of a dense body, the activation of osteoblasts and the like is limited due to diffusion of cytokines and growth factors released from macrophages. When the apatite carbonate is a porous body but does not hold through-holes extending in one direction, that is, when the porous body is a foam-like porous body, the diffusion of cytokines and growth factors released from macrophages is limited as compared with the surface of dense apatite carbonate, but since the diffusion is three-dimensional, the local existence of cytokines and growth factors released from macrophages is limited. On the other hand, it is considered that the apatite carbonate honeycomb retains through-holes extending in one direction, and locally retains cytokines and growth factors released from macrophages. As a result, it is considered that osteoblasts and the like are highly activated, and that blood vessels are formed which are necessary for bone formation and maintenance of the function of the formed bone.

Industrial applicability

The medical honeycomb structure of the present invention satisfies the requirements that are desired for a medical material, that is, (1) the adhesion or bondability of cells or tissues to the surface of the material is excellent, (2) the tissue capable of regeneration/reconstruction orientation, (3) the mechanical strength is excellent, (4) the tissue is rapidly replaced with a desired tissue when used as a tissue substitute material, (5) the honeycomb structure can be produced at low cost; can be widely used in the medical field or the medical-related field.

Description of the reference numerals

10 the medical honeycomb structure of the present invention

11 through hole

12 partition wall

13 peripheral side wall

14 honeycomb structure having outer peripheral side wall

15 through hole entrance

16 through hole groove

Claims

1. A medical honeycomb structure comprising a plurality of through holes extending in one direction,

the outer peripheral side part of the utility model is provided with: a through hole groove formed by the defect of the side wall of the through hole; and a through-hole inlet adjacent to the through-hole groove,

an inclined surface inclined with respect to a penetrating direction of the through hole is formed on the outer peripheral side portion, the through hole groove and the through hole inlet are formed at least on the outermost layer of the outer peripheral side portion and the 2 nd outer layer inside the outermost layer,

the ratio of the length of the through hole groove in the longitudinal direction to the length of the through hole groove in the width direction is 3.0 or more,

the diameter of the through hole is 5-400 μm,

the thickness of the partition walls of the through hole is 10 μm or more and 300 μm or less,

the medical honeycomb structure is formed from a composition containing at least one calcium compound selected from the group consisting of calcium phosphate, calcium carbonate, calcium sulfate, and calcium-containing glass.

2. The medical honeycomb structure according to claim 1, wherein a ratio of the number of through-hole entrances to the number of through-holes in the outermost layer to the number of through-holes is 0.05 or more.

3. The medical honeycomb structure according to claim 1, wherein the ratio of the uneven surface of the outer peripheral side surface on which the through-hole grooves and the through-hole inlets are formed is 10% or more.

4. The medical honeycomb structure according to claim 1, wherein a through-hole penetrating through a side wall of the through-hole is provided.

5. The medical honeycomb structure according to claim 1, wherein a ratio of a diameter of the through-hole to a thickness of the partition walls of the through-hole is 0.2 or more and 20 or less.

6. The medical honeycomb structure according to claim 1, wherein the thickness of the outer peripheral side wall of the outer peripheral side portion is 300 μm or less.

7. The medical honeycomb structure according to claim 1, wherein a ratio of a length of the through-holes in a longitudinal direction to a diameter thereof is 3 or more.

8. The medical honeycomb structure according to claim 1, which is 10^-8m³Above and 10^-3m³The following blocks.

9. The medical honeycomb structure according to claim 1, which is formed of a composition containing at least one selected from the group consisting of apatite, β -tricalcium phosphate, α -tricalcium phosphate and octacalcium phosphate.

10. The medical honeycomb structure according to claim 1, which is formed of a composition containing a carbonic apatite.

11. The medical honeycomb structure according to claim 1, which is formed of a composition containing a polymer material.

12. The method for manufacturing a medical honeycomb structure according to any one of claims 1 to 11, comprising the steps of:

a structure-with-outer-wall manufacturing step of extruding a material through a honeycomb structure forming die to manufacture a honeycomb structure having an outer peripheral side wall; and

and an outer peripheral side portion processing step of removing at least a part of the outer peripheral side wall of the honeycomb structure having the outer peripheral side wall to form a through-hole groove and a through-hole entrance in the outer peripheral side portion.

13. A method for producing a crushed product of a medical honeycomb structure according to any one of claims 1 to 11, comprising:

a structure-with-outer-wall manufacturing step of extruding a material through a honeycomb structure forming die to manufacture a honeycomb structure having an outer peripheral side wall;

14. A method for producing a medical honeycomb structure according to any one of claims 1 to 11, which comprises a composition containing apatite carbonate, the method comprising the steps of:

a degreasing step of degreasing the honeycomb structure;

in the outer peripheral side portion processing step, at least a part of an outer peripheral side wall of the honeycomb structure having the outer peripheral side wall is removed, and a through-hole groove and a through-hole inlet are formed in the outer peripheral side portion.

15. A method for producing a medical honeycomb structure according to any one of claims 1 to 11, which comprises a composition containing apatite carbonate, the method comprising the steps of:

a degreasing step of degreasing the honeycomb structure; and